The esters of the present invention are used as intermediates for the preparation of the corresponding 1,8-dialkyl-1-3,4,9-tetrahydropyrano (3,4-b)-indole-1-acetic acids, which include etodolac, an anti-inflammatory and analgesic compound reported first by Demerson et al., U.S. Pat. No. 3,939,178.
Throughout, preparation of these esters has been previously described in U.S. Pat. Nos. 3,939,178; 4,012,417; 4,585,877; and several related patents. These esters are prepared from the corresponding 7-substituted tryptophol and alkyl propionylacetate. U.S. Pat. Nos. 3,939,178 and 4,012,417 disclose reaction of substituted tryptophols with keto ester to produce pyrano (3,4-b) indoles. Suitable solvents described are benzene, toluene, diethyl ether, dioxan, tetrahydrofuran, methylene dichloride, carbon tetrachloride and the like. Benzene and tetrahydrofuran are the preferred solvents.
Suitable acid catalysts which may be used for this condensation are the type of catalysts used in Fischer Indole Synthesis and include p-toluenesulfonic acid, phosphorus pentoxide, boron trifluoride, zinc chloride, hydrochloric acid and sulfuric acid and the like. Preferred catalysts being p-toluenesulfonic acid, boron trifluride and phosphorus pentoxide. According to Example 477 of U.S. Pat. No. 3,939,178, etodolac ethyl ester is produced by the reaction of 7-ethyltryptophol and the keto ester, ethyl propionyl acetate, using benzene as a solvent and p-toluenesulfonic acid as the catalysts. The product so obtained is purified by column chromatography, which is hydrolysed under alkaline conditions to give etodolac.
U.S. Pat. No. 4,585,877 discloses reaction of the methyl ester of 3-methoxy-2-pentenoic acid with 7-ethyltriptophol using dichloromethane as a solvent and boron trifluoride ethereate as the catalyst.
The methods described in the prior art suffer from several disadvantages:
Firstly, the use of strong acid catalysts exposes the desired product to other acid catalysed reactions resulting in the formation of impurities. In order to minimise the impurities, the ester is either purified by column chromatography before hydrolysis or the hydrolyzed product is purified at the cost of the yields and overall efficiency of the process. Moreover, the purification by column chromatography is very cumbersome and is disadvantageous at a commercial scale because of its efficiency and higher manufacturing costs.
Secondly, the use of carcinogenic solvents like benzene, tetrahydrofuran and strong acids like p-toluenefonic acid, boron trifluoride ethereate or sulfuric acid at industrial scale involves health hazards and poses serious environmental problems.
For purposes of patient safety, it is highly desirable to limit the amount of residual solvent present in any medicament administered to a patient. With this objective in mind, International Regulatory bodies impose stringent limits on residual solvents and categorize solvents in various classes depending upon their toxicity. The solvents used in prior art have been categorized in Class I category, which are highly toxic.
Therefore, the aim of the present invention is to provide an efficient process for the preparation of the esters of 1,8-disubstituted - 1,3,4,9-tetrahydropyrano (3, 4,6)- indole-1-acetic acid of formula I (as shown in the accompanied drawings), which process avoids the use of corrosive solvents, strong corrosive acids and gives a product of high purity and yield.
In general, molar equivalent proportions of 7-alkyltryptophol and B-ketoester is used. More preferably, 0.9-1.2 molar ratio of B-keto ester with respect to 7-alkyltriptophol is used but varying amounts of molar ratios are within the scope of this invention.